Inherited retinal degenerations (IRD) are the leading cause of irreversible blindness in young adults in the United States. The genetic basis of recessive IRD is known only in about 50% of cases. Furthermore, little is known about the molecular mechanism underlying these diseases. Cures are currently unavailable for these diseases. However, gene therapy clinical trials for Leber's congenital amaurosis have been reported to be successful and gene-based pre-clinical studies of IRD treatments were found to be effective. Nevertheless, the lack of information on the underlying cause of IRD in the remaining half of cases and the paucity of knowledge on the pathways leading to these diseases impedes the development of therapies to treat these conditions. Until recently, the search for the genetic cause of IRD was limited to the coding region comprising 3% of the genome leaving the remaining 97% unexplored. In addition, prioritization and interpretation of candidate variants has been challenging due to the lack of efficient methodologies. In this proposal we aim to identify the genetic cause of disease in the remaining 50% of cases and understand the pathways involved in causing IRD. To achieve our goals, we will build on the opportunity we have to sequence the whole genomes (WGS) of 500 individuals from IRD pedigrees and the exome sequences (WES) generated on 54 pedigrees in the previous grant cycle, representing 230 unrelated pedigrees/patients. We propose to analyze the WGS and WES to identify the novel genes and associated pathways leading to IRD pathology by: (1) identifying putative candidate variants in both coding and non-coding regions, (2) using computational analysis that integrates existing data; publicly available genomes, epigenomes, transcriptomes and other large data sets relevant to IRD; and experimental data including the molecular expression profiles of relevant retinal cells differentiated from patient induced pluripotent stem cells (hiPSC) and (3) performing molecular and biochemical analyses of putative causal variants using patient iPSC based disease-in-dish models and CRISPR-Cas9 system based genome edited mouse models. These studies will provide a molecular profile of the IRD genome, identify novel genes involved in causing IRD, enhance our understanding of the biological pathways leading to retinal degeneration, and establish a molecular-network based approach for finding causal variants in patients with IRD. These studies will also enable the development of genetic tests for patients and precision medicine strategies based on pathways associated with RD pathology.